Cigarette smoking combines with genetic variants to regulate FOXN3 and associate with bladder cancer risk

FOXN family genes (FOXNs) have a significant role in the progression of various malignancies; nevertheless, the relationship between their genetic variations and the risk of bladder cancer is yet insufficiently comprehended. This study included 580 bladder cancer patients and 1,101 healthy controls, evaluated for 8,695 single nucleotide polymorphisms (SNPs) in FOXNs. The rs10484024 T > C variant in FOXN3 was identified as a significant risk factor for bladder cancer (OR = 1.18, 95% CI: 1.02-1.36, P = 2.72 × 10^- 2). Further investigation reveals a strong interaction between this locus and smoking (P_interaction = 3.50 × 10^- 2), and bladder cancer risk is much higher in smokers carrying the C allele (OR = 1.93, 95% CI: 1.39-2.71, P = 1.13 × 10^- 4). Functional annotation results suggest that rs10484024 is likely reducing FOXN3 expression by affecting the remote regulation of RNA-binding protein binding sites and enhancers/promoters. The TCGA study, in conjunction with GSE3167, confirmed that the dysregulation of FOXN3 expression was associated with altered mutation frequency in KMT2C somatic cells and the modulation of cell cycle-related pathways. The data suggest that rs10484024 may promote bladder cancer by regulating FOXN3 expression and worsening cell cycle dysregulation and somatic mutation accumulation. This study established, for the first time, an association between genetic variation in the FOXN3 gene and bladder cancer risk, demonstrating a substantial interaction with smoking, suggesting that FOXN3 may serve as a novel biomarker and intervention target for bladder cancer.